FORMATION OF PROMUTAGENIC METHYLATION DAMAGE IN TISSUE-DNA OF MICE TREATED WITH ANTISCHISTOSOMAL AGENTS

The existence of the promutagenic methylation damage O-6-MedG has been measured at various time intervals in different tissue DNAs of mice received a single therapeutic dose of various antischistosomal agents (hycanthone, oxaminiquine and metrifonate). Liver-DNA exhibited the highest levels of O-6-MedG in all treated animals while, spleen DNA contained the lowest. The three antischistosoml agents tested seemed to exert the peak concentrations of their alkylating metabolites over a period of several hours following the administration. In mice which had received hycanthone, liver-DNA contained readily detectable amounts of O-6-MedG by 6 h post-treatment (0.089 mol O-6-MedG/mol dG) and by the end of 48 h, this was decreased by about 3-fold to reach a level of 0.026 mu mol/mol dG. In intestinal-DNA, however, O-6-MedG was formed more slowly and contained about half the level of that found in the liver-DNA. In the tissue-DNA of animals which had received oxaminiquine, the highest level of O-6-MedG was observed at 6 h after administration and at a 24-h time point, the adduct dramatically decreased in the liver and intestine-DNA to undetectable values. In neither tissues was there any evidence for O-6-MedG accumulation in the DNA at the end of a 48-h post-treatment. A pattern of O-6-MedG, almost similar to that of oxaminiquine, was also observed in tissue-DNA of mice pretreated with metrifonate. These results demonstrate that treatment with antischistosomal agents leads to the formation of highly promutagenic alkylated lesions in the tissue-DNA. The implication of Such existence for antischistosomal-induced toxicity and carcinogenicity are discussed.